1. Field of the Invention
The invention relates to methods of sterilizing liquid adhesive and microbial sealant compositions using X-ray irradiation. In particular, the invention relates to a method of sterilizing liquid adhesives in a sealed container at a dose of about 5 to about 40 kGy. In addition, the invention relates to a method of utilizing X-ray for the first time to sterilize liquid adhesive or microbial sealant compositions, which can provide an extended shelf life of at least two years after X-ray sterilization.
2. Description of the Prior Art
It is well-known that cyanoacrylate adhesives can be used for bonding tissue in surgical and medical procedures. In these applications, the adhesive composition can be used to close wounds, as well as to cover and protect surface injuries such as lacerations, abrasions, burns, sores and other open surface wounds. Additionally, liquid cyanoacrylate compositions recently have been found useful as liquid microbial sealant drapes to immobilize the bacteria before surgery. The cyanoacrylate adhesives are liquid monomers that polymerize on contact with tissue surfaces in an exothermic reaction creating a strong yet flexible film. This polymer film is generally formed rapidly. When cyanoacrylate adhesive compositions are used in the medical field, the adhesive compositions should be sterile. Several methods are known for sterilizing cyanoacrylate monomeric compositions.
Dry heat is one of the earliest sterilization methods used for sterilizing cyanoacrylate adhesives as disclosed in U.S. Pat. No. 5,874,044 to Kotzev; and U.S. Patent Application Publication Nos. 20080311323 and 20060062687 to Morales, which disclose using relatively lower temperatures. A disadvantage of dry heat sterilization is that the required temperatures can cause premature polymerization of the cyanoacrylate monomers.
Other known methods for sterilizing cyanoacrylate monomers include microwave sterilization, visible light sterilization and irradiation sterilization. Visible light sterilization is taught in U.S. Pat. No. 6,579,916 to Askill, wherein the disclosed method uses visible light irradiation having wavelengths of from 390 nanometers (nm) to 780 nm, at a dose of from about 0.01 to 50 joules/cm2, at room temperature.
Electron beam (e-beam) irradiation sterilization is one of the most common methods for sterilizing cyanoacrylate compositions. U.S. Pat. No. 6,143,805 to Hickey et al. teaches sterilizing cyanoacrylate liquid adhesive compositions using e-beam irradiation which causes no substantial initiation of polymerization of the cyanoacrylate composition and results in compositions suitable for application to open wounds. U.S. Pat. No. 6,248,800 to Greff et al. discloses a method for sterilizing cyanoacrylate ester compositions using e-beam irradiation at room temperature, at a dose preferably from about 15 to 20 kGy, and a required average bulk density of the materials comprising the packaging element of less than about 0.2 gm/cm3. U.S. Patent Application Publication No. 20070248486 discloses e-beam sterilization of cyanoacrylate ester compositions at doses as low as about 1 to about 5 kGy. A disadvantage to using e-beam irradiation for sterilizing cyanoacrylates is that it can also result in pre-mature polymerization of the monomers thus affecting both the shelf life and the performance of the product cyanoacrylate adhesives or sealants.
Gamma irradiation is yet another known method for sterilizing cyanoacrylate adhesives. U.S. Pat. No. 3,704,089 to Stehlik sterilizes cyanoacrylate adhesives by first freezing cyanoacrylate compositions into a solid state at very low temperatures (below −30° C.), then exposing them to gamma irradiation. U.S. Pat. No. 5,530,037 to McDonnell et al. teaches sterilizing cyanoacrylate adhesive compositions for medical use by using a minimum dose of 25 kGy gamma irradiation at room temperature. Such relatively high doses of aggressively penetrating gamma irradiation can easily cause changes in the formulated cyanoacrylate adhesive compositions resulting in unwanted and potentially harmful substances that negatively impact the ability of the adhesive to perform. Attempts to minimize these changes typically require the addition of very high levels of inhibitors, which can increase the toxicity of the mixture and increase the toxic by-products formed upon gamma irradiation. The use of high doses of toxic gamma irradiation to effect sterilization also raises safety concerns for workers who are exposed long term to this radiation.
Both gamma and electron beam irradiation sterilize medical products by destroying microorganisms with ionizing radiation. High energy X-rays, which are generated using high powered beams from electron accelerators, sterilize similarly with ionizing radiation. However, it is surprising that X-rays have never been used to sterilize cyanoacrylate compositions for medical use. This may partly be due to the fact that X-ray sterilization is historically still a young technology compared to processes using gamma and e-beam irradiation, which have been used for some time. Since first proposed about 40 years ago, X-ray sterilization of medical products has been investigated experimentally and theoretically by researchers and accelerator manufacturers. And while commercial use of X-ray sterilization began about 20 years ago, it has not been readily adopted due to the low output power of early X-ray generators and the known sensitivity of cyanoacrylates to irradiation which induces premature polymerization.
X-rays have many advantages over gamma and electron beam irradiation. X-rays are short-wavelength, high-frequency electromagnetic photons, which are emitted by high-energy electrons when they are deflected by atomic nuclei. X-rays at 5 MeV (million electron volts) and 7 MeV provide a greater penetration property than gamma irradiation from a cobalt-60 source. Gamma irradiations are emitted in all directions from a cobalt source, while x-rays are concentrated in the direction of the incident electron beam. The high intensity in the forward direction improves the efficiency of x-ray. High-energy X-rays are ideal for sterilizing large packages of medical devices and provide excellent dose uniformity while treating full pallets of medical devices compared to gamma sterilization. X-rays are generated by a machine, while cobalt producing reactors of gamma rays will require expensive upgrades in the coming years. Compared to gamma irradiation, X-ray sterilization does not require radioactive transport or waste management. Based on the regulatory rules, transportation of radioactive cobalt-60 is presently challenging and relevant regulations are generated more and more every year. The flexibility of X-rays is another compelling reason to use this sterilization method for medical devices. Compared to gamma, X-rays adapt better to changing volumes of materials to be sterilized. Source loading of gamma rays is prepared by detailed calculations, which is fixed and very difficult to modify, while x-ray beam configurations can be changed by simply a mouse click. In addition, X-ray sterilization induces a small temperature variation which does not damage plastic materials, often used to contain the compositions.
High-power and high-energy X-ray accelerators have recently been developed, which facilitate the industrial and medical application of X-ray sterilization. U.S. Pat. No. 6,738,451 to Avnery discloses an apparatus used for sterilizing medical instruments more quickly and thoroughly. The X-ray beam emitter includes a vacuum chamber having a target window. An electron generator is positioned within the vacuum chamber for generating electrons to form X-rays. U.S. Patent Application Publication No. 20070237296 to Wyatt et al. discloses a sterilization device that consists of at least one planar X-ray source and an irradiation chamber which receives X-rays. The planar x-ray source is composed of an electron target that receives electrons from the cathode, a field emission cathode and an applied voltage for accelerating electrons from the cathode to the target. While the early unit costs of X-ray sterilization may be comparable to other treatment methods, in the long term, X-ray sterilization will be more cost effective.
The US Food and Drug Administration (FDA) has approved food irradiation with X-ray energies up to 7.5 MeV. Lately, x-rays have been extensively used to sterilize large quantities of mail. U.S. Patent Application Publication No. 20070261986 to Bublewitz et al. discloses a method for sterilizing medical single-component or multi-component impression materials. The components of the impression materials are contained into a primary package, which are sterilized by heat sterilization. The sterilized components in the primary package are introduced into a secondary package, which are then sterilized by a suitable gas sterilization, or irradiation sterilization such as x-ray sterilization. X-ray has been investigated to sterilize health care products. Radiation sensitivities and the dose rate effects of B. pumilus and B. subtilis were examined for x-rays and cobalt-60 gamma rays. Compared to gamma sterilization, the results provided the supporting data for possible sterilization of medical devices by x-rays (Sato et al. Radia. Phys. Chem. 42, 621-624, 1993). Additionally, radiological safety of medical devices sterilized with x-rays at 7.5 MeV was investigated by Gregoire et al. who concluded that sterilization with X-rays at 7.5 MeV can be considered safe from the standpoint of public health and personal safety if certain precautions are taken (Gregoire et al. Radia. Phys. Chem. 67, 149-167, 2003).
In spite of the fact that X-rays have been proposed for sterilizing food and medical devices, X-rays have never been used to sterilize cyanoacrylate adhesive and microbial sealant compositions. Compared to gamma and e-beam sterilization, X-ray irradiation provides the many advantages as described above. It would be advantageous and beneficial to the industry to provide an x-ray irradiation method of sterilizing cyanoacrylate compositions. Therefore, it is an object of the present invention to apply X-ray irradiation for the first time to sterilize cyanoacrylate monomer compositions, which have a useful extended shelf life, making them particularly suitable for medical applications.